Chemistry:Isoprenaline

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Short description: Medication for slow heart rate
Isoprenaline
INN: Isoprenaline
Isoprenaline.svg
Clinical data
Trade namesMany[1]
Other namesIsoproterenol (USAN US)
MedlinePlusa601236
Pregnancy
category
  • AU: A
  • US: C (Risk not ruled out)
Routes of
administration		Inhalation (80–120 μg), intravenous injection (IV)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life~2 minutes
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC11H17NO3
Molar mass211.261 g·mol−1
3D model (JSmol)
  (verify)

Isoprenaline, or isoproterenol, is a medication used for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma. It is a non-selective β adrenoceptor agonist that is the isopropylamine analog of epinephrine (adrenaline).[2]

Medical uses

It is used to treat heart block and episodes of Adams–Stokes syndrome that are not caused by ventricular tachycardia or fibrillation, in emergencies for cardiac arrest until electric shock can be administered, for bronchospasm occurring during anesthesia, and as an adjunct in the treatment of hypovolemic shock, septic shock, low cardiac output (hypoperfusion) states, congestive heart failure, and cardiogenic shock.[2] It is also used to prevent Torsades de Pointes in patients with long QT refractory to magnesium and to treat patients with intermittent Torsades de Pointes refractory to treatment with magnesium.[3]

Historically, it was used to treat asthma via metered aerosol or nebulizing devices; it was also available in sublingual, oral, intravenous, and intramuscular formulations.[4] The U.S. National Asthma Education and Prevention Program Expert Panel recommends against its use as a nebulizer for acute bronchoconstriction.[5]

Isoprenaline can also ameliorate the impairment of intestinal stem cells mediated by β2-adrenoreceptors after chemotherapy.[6]

Contraindications

It should not be used in people with tachyarrhythmias (except in special circumstances),[7] tachycardia or heart block caused by digitalis poisoning, ventricular arrhythmias which require inotropic therapy, or with angina.[2]

Adverse effects

Adverse effects of isoprenaline include nervousness, headache, dizziness, nausea, visual blurring, tachycardia, palpitations, angina, Adams-Stokes attacks, pulmonary edema, hypertension, hypotension, ventricular arrhythmias, tachyarrhythmias, difficulty breathing, sweating, mild tremors, weakness, flushing, and pallor.[2] Isoproterenol has been reported to cause insulin resistance leading to diabetic ketoacidosis.[8]

Pharmacology

The adverse effects of isoprenaline are also related to the drug's cardiovascular effects. Isoprenaline can produce tachycardia (an elevated heart rate), which predisposes people who take it to cardiac arrhythmias.[4]

Pharmacodynamics

Isoprenaline is a β1 and β2 adrenoreceptor agonist and has almost no activity on alpha adrenergic receptors at low levels.[4] However, at higher concentrations, isoprenaline can evoke α-AR-mediated responses.[9][10] Its agonist effects at TAAR1 provide it with pharmacodynamic effects that resemble those of the endogenous trace amines, like tyramine.[11]

Isoprenaline's effects on the cardiovascular system (non-selective) relate to its actions on cardiac β1 receptors and β2 receptors on smooth muscle within the tunica media of arterioles. Isoprenaline has positive inotropic and chronotropic effects on the heart. β2 adrenoceptor stimulation in arteriolar smooth muscle induces vasodilation. Its inotropic and chronotropic effects elevate systolic blood pressure, while its vasodilatory effects tend to lower diastolic blood pressure. The overall effect is to decrease mean arterial pressure due to the β2 receptors' vasodilation.[12]

The isopropylamine group in isoprenaline makes it selective for β receptors. The free catechol hydroxyl groups keep it susceptible to enzymatic metabolism.[13]

Pharmacokinetics

The plasma half-life for isoproterenol is approximately two to five minutes. It is degraded enzymatically via catechol O-methyltransferase (COMT) primarily in the liver and excreted in the urine as sulfated conjugates.[14][15]

Chemistry

It is structurally related to epinephrine.[2]

History

It was first approved in the US in 1947.[4] Between 1963 and 1968 in England, Wales, Scotland, Ireland, Australia, and New Zealand there was an increase in deaths among people using isoprenaline to treat asthma. This was attributed to overdose: the inhalers produced in that area were dispensing five times the dosage dispensed by inhalers produced in the US and Canada, where the deaths were not observed.[16][17]

Society and culture

Brands

Isoprenaline is marketed under many brand names worldwide, including Aleudrina, Asthpul, Iludrin, Isomenyl, Isuprel, Neo-Epinine, Neodrenal, Proternol, and Saventrine.[1] It is also marketed as a combination drug with cromoglicic acid as Frenal Compositum, in combination with pronase as Isopal P, and in combination with atropine as Stmerin D.[1]

References

  1. ↑ 1.0 1.1 1.2 "Isoprenaline international brands". Drugs.com. https://www.drugs.com/international/isoprenaline.html. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Label: Isoproterenol hydrochloride injection, solution". NIH DailyMed. September 10, 2013. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a58f95fa-18f9-4938-8e3f-f33244f68298. 
  3. ↑ "Torsade de Pointes". StatPearls. Treasure Island (FL): StatPearls Publishing. August 2022. NBK459388. 
  4. ↑ 4.0 4.1 4.2 4.3 (in en) Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science & Business Media. 2003. pp. 541–542. ISBN 978-1-59259-654-6. https://books.google.com/books?id=dwMyBwAAQBAJ&pg=PA541. 
  5. ↑ National Asthma Education and Prevention Program Expert Panel (August 28, 2007). "Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma". NIH National Heart, Lung, and Blood Institute. https://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf. 
  6. ↑ "Isoprenaline protects intestinal stem cells from chemotherapy-induced damage". British Journal of Pharmacology 177 (3): 687–700. February 2020. doi:10.1111/bph.14883. PMID 31648381. 
  7. ↑ "Electrical storms in Brugada syndrome successfully treated with isoproterenol infusion and quinidine orally". Netherlands Heart Journal 15 (4): 151–155. April 2007. doi:10.1007/BF03085972. PMID 17612676. 
  8. ↑ "Isoproterenol Induced Insulin Resistance Leading to Diabetic Ketoacidosis in Type 1 Diabetes Mellitus". Case Reports in Endocrinology 2018: 4328954. 2018. doi:10.1155/2018/4328954. PMID 30647979. 
  9. ↑ "Reactions of strips of rabbit aorta to epinephrine, isopropylarterenol, sodium nitrite and other drugs". The Journal of Pharmacology and Experimental Therapeutics 108 (2): 129–143. June 1953. PMID 13062084. https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=13062084. 
  10. ↑ "Isoproterenol acts as a biased agonist of the alpha-1A-adrenoceptor that selectively activates the MAPK/ERK pathway". PLOS ONE 10 (1): e0115701. 21 January 2015. doi:10.1371/journal.pone.0115701. PMID 25606852. Bibcode: 2015PLoSO..1015701C. 
  11. ↑ "Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists". PLOS ONE 6 (10): e27073. October 2011. doi:10.1371/journal.pone.0027073. PMID 22073124. Bibcode: 2011PLoSO...627073K. "Table 1. EC50 values of different agonists at hTAAR1, hADRB1 and hADRB2". 
  12. ↑ (in pl) Farmakologia. Wydawnictwo Lekarskie PZWL. 2017. p. 36. ISBN 978-83-200-5368-5. 
  13. ↑ "Notes - Medicinal Chemistry of the Peripheral Nervous System - Adrenergics and Cholinergic". Pharmaxchange. January 27, 2011. http://pharmaxchange.info/notes/medicinal_chemistry/adrenergics_cholinergics.html. 
  14. ↑ "Pharmacology of Cardiovascular Drugs". Critical Heart Disease in Infants and Children. 2019. pp. 192–212.e6. doi:10.1016/B978-1-4557-0760-7.00019-X. ISBN 978-1-4557-0760-7. 
  15. ↑ "Isoproterenol". StatPearls. StatPearls Publishing. 2023. NBK526042. 
  16. ↑ "Epidemiologic studies of beta agonists and asthma deaths". Epidemiologic Reviews 20 (2): 173–186. 1998. doi:10.1093/oxfordjournals.epirev.a017979. PMID 9919437. 
  17. ↑ "Three generations of ongoing controversies concerning the use of short acting beta-agonist therapy in asthma: a review". The Journal of Asthma 45 (1): 9–18. 2008. doi:10.1080/02770900701495512. PMID 18259990. 



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